Our work in the last two years has led to the realization that antigen-independent adhesion is a critical early event in T lymphocyte interactions with other cells, and we hypothesized that there are two molecular pathways by which such interactions occur: T cell CD2 (T11, E-rosette receptor) interacting with its ligand LFA-3 and T cell LFA-1 interacting with an unknown ligand. This year's work has confirmed and extended those concepts. Biochemical studies of purified CD2 and LFA-3 have confirmed the binding of each to the other -- corroborating our inference based on functional studies that LFA-3 is the ligand for CD2. A particularly interesting example of adhesion mediated by these two pathways is the spontaneous rosetting of Reed- Sternberg cells with human peripheral blood T cells. Furthermore, LFA-3 has been shown to be the erythrocyte ligand which mediates autologous rosetting. The concept of two pathways of adhesion has been extended to indicate its relevance to T-cell mediated cytotoxicity (CML) as well as conjugate formation. Studies of CML as well as adhesion demonstrate functionally that ICAM-1 is the principal ligand for LFA-1 in T cell interaction with some targets, but suggest that other as yet unidentified ligands are involved in interactions with other targets. Because of the functional importance of these adhesion molecules, we have carefully investigated their expression on peripheral blood T cells. Our studies demonstrate that expression of LFA-3, CD2, and LFA-1 is increased on a major subset of peripheral blood T cells with the functional properties of memory cells and raise the possibility that such enhanced expression of these functionally important molecules may contribute to the enhanced responsiveness of memory T cells.